PRESS-NEWS.org - Press Release Distribution
PRESS RELEASES DISTRIBUTION

Epigenetic pathway and new drug show promise in reversing a hard-to-treat childhood cancer

Mixed lineage leukemias rely on epigenetic changes to grow and survive; new molecule shows promise for targeting these changes therapeutically

2011-07-12
(Press-News.org) A difficult-to-treat form of childhood leukemia relies on changes in the structure of DNA – so-called epigenetic changes – to wreak genomic havoc within white blood cells, according to one of two studies conducted by a research team at Children's Hospital Boston and Dana-Farber Cancer Institute. Together with collaborators from a biotechnology company, the same team also showed that a new drug that blocks these changes could deactivate cancer-promoting genes and halt the growth of this cancer.

These studies, reported in a pair of papers in the July 11, 2011 issue of Cancer Cell, are the first to therapeutically target a core epigenetic vulnerability in the subgroup of leukemias caused by a "reshuffling" or rearrangement of the mixed lineage leukemia (MLL) gene.

"We have known for a while that MLL leukemias arise from widespread alterations not in the genetic code itself, but in the structure of the DNA and the proteins associated with it," according to Scott Armstrong, MD, PhD, a pediatric oncologist at Children's and Dana-Farber. "We now show that these epigenetic changes indeed turn on cancer-promoting genes within white blood cells, and ultimately cause the leukemia.

"Even more importantly," he continued, "we show that we can reverse the process."

While childhood leukemia is one of the great success stories in cancer therapy, those caused by MLL gene rearrangements stand out as devastating exceptions. In these cancers, a portion of chromosome 11 (where the MLL gene resides) breaks off and fuses with parts of other chromosomes to create new fusion proteins. The fusion proteins subvert the normal function of the MLL gene and activate a set of leukemia-causing genes.

MLL gene rearrangements account for approximately 10 percent of children and adults diagnosed with acute lymphoblastic or acute myeloid leukemias; most of these patients do not respond well to standard leukemia treatments.

"The success rates for treating other childhood leukemias has reached 80 or 90 percent," Armstrong said. "However, we still only achieve about 50 percent success in treating MLL-rearranged leukemias. We need to find better ways of caring for these patients, and these results give us confidence that we are heading in the right direction."

Armstrong had previously shown that MLL-rearranged leukemia cells have a unique pattern of histone methylation, a specific kind of epigenetic modification, caused by an enzyme called Dot1l. This enzyme, which is recruited to cancer-promoting genes by the MLL-fusion protein, attaches a methyl group to a particular amino acid on a histone (a scaffolding protein that helps manage gene activation) called histone H3.

In the first of the two Cancer Cell papers, Armstrong, along with Kathrin Bernt, MD, and Andrew Kung, MD, PhD, of Children's and Dana-Farber, confirms that genes targeted by a MLL fusion protein called MLL-AF9 are associated with inappropriately methylated histone H3 proteins. By genetically inactivating Dot1l, the team could eliminate the MLL-specific histone methylation and gene expression patterns in cells from a mouse model of the disease. In addition, they found that mice injected with leukemia cells lacking Dot1l did not develop leukemia, in contrast to those injected with leukemia cells possessing active Dot1l.

"Our previous work suggested that Dot1l was the culprit behind the abnormal methylation patterns in MLL-rearranged cells," Armstrong noted. "We now know that these leukemias fully rely on this enzyme and the methylation pattern it generates in order to persist and grow.

"While methylation tags on histones are very difficult to manipulate directly," he added, "Dot1l is much easier to target therapeutically."

The second Cancer Cell paper, co-authored by Armstrong, Bernt, Kung and collaborators at the biotechnology company Epizyme, takes the Dot1l findings a step further by showing that a small molecule called EPZ004777, which inhibits the enzyme, does indeed eliminate the abnormal methylation pattern in MLL cells. In cell-based laboratory models, the effects of treatment with EPZ004777 mirrored those obtained by inactivating Dot1l in genetically engineered "knockout" mice, while selectively causing MLL-rearranged leukemia cells to die off in about two weeks' time. Moreover, mice with MLL-rearranged leukemia showed increased survival when treated with EPZ004777.

"The oncology field is very excited about epigenetic inhibition right now," Armstrong said. "Enzymes like Dot1l that influence epigenetics are overactive in many cancers. What we've done is show that we can block one of these enzymes and get very specific anti-tumor activity in a previously very hard-to-treat disease."

###

The two studies were supported by grants from the National Cancer Society, the Leukemia and Lymphoma Society, Gabrielle's Angel Foundation, the National Cancer Institute, the National Heart Lung and Blood Institute, and the William Lawrence and Blanche Hughes Foundation.

Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 12 members of the Institute of Medicine and 13 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 395 bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about research and clinical innovation at Children's visit Vector blog.

(DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women's Hospital as Dana-Farber/Brigham and Women's Cancer Center and it provides pediatric care with Children's Hospital Boston as Dana-Farber/Children's Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding.

END



ELSE PRESS RELEASES FROM THIS DATE:

Neural stem progenitor cell transplantation’s potential to aid spinal cord injury tested

2011-07-12
Tampa, Fla. (July. 11, 2011) – A study published in the current issue of Cell Transplantation (20:5) investigating optimal routes for transplanting neural stem/progenitor cells (NS/PCs) in animal models of spinal cord injury (SCI) has demonstrated that intralesional (IL) injection conferred benefits over intravenous injection (IV) and intrathecal (IT) injection. The study, by a team of Keio University (Japan) researchers, is now freely available on-line at http://www.ingentaconnect.com/content/cog/ct/ . "Spinal cord injury usually results in severe, paralytic damage ...

Just like teens, parents get personal on Facebook

2011-07-12
They may not dress like Justin Bieber or Selena Gomez, but parents are a whole lot like their teenagers when it comes to their behaviour on Facebook. That's the finding of a new study by University of Guelph researchers. Parents are just as likely as their kids to disclose personal information on the social networking site, according to the research, which will be published in the journal Social Psychological and Personality Science and is available online now. And (gasp!) mom and dad are just as susceptible to the need for popularity. "Facebook is not just a phenomenon ...

Sertoli cells show promise for therapeutics

2011-07-12
Tampa, Fla. (July 11, 2011) – Two papers published in the current issue of Cell Transplantation (20:5), now freely available on-line at http://www.ingentaconnect.com/content/cog/ct/, highlight the therapeutic potential of human Sertoli cells that are present in the testes and are also called "nurse" or "mother" cells because they nurture the developing sperm cells. Sertoli cells form the blood-testes barrier that separates the blood compartment of the testes from the compartment of the seminiferous tubules. Once differentiated to form the blood-testes barrier, Sertoli cells ...

The truth about cats and dogs: Pets are good for mental health of 'everyday people'

2011-07-12
WASHINGTON – Pets can serve as important sources of social and emotional support for "everyday people," not just individuals facing significant health challenges, according to research published by the American Psychological Association. And, the study found, pet owners were just as close to key people in their lives as to their animals, indicating no evidence that relationships with pets came at the expense of relationships with other people, or that people relied more on pets when their human social support was poorer. Psychologists at Miami University and Saint ...

Writing DNR orders takes longer, death more likely when surrogate decision-maker involved

Writing DNR orders takes longer, death more likely when surrogate decision-maker involved
2011-07-12
INDIANAPOLIS – Indiana University and Regenstrief Institute researchers report that it takes significantly longer for orders to forgo resuscitation in the event of cardiac arrest to be written for patients who had that decision made for them by a surrogate decision-maker compared to patients who made their own decisions, even though patients with a surrogate were sicker and the resuscitation issue might arise sooner. Among patients who died, patients with a surrogate had a shorter time frame between writing the DNR order and time of death compared to patients who made ...

Biofilters reduce carbon footprint of old landfill sites

2011-07-12
Researchers in the US are testing biofilter systems as a viable alternative to releasing methane from passive landfill vents into the atmosphere. The technology could reduce the overall impact of old landfills on global warming. Details are reported in the current issue of the International Journal of Environmental Engineering. Organic matter rotting in smaller, old landfill sites generates a slow trickle of the potent greenhouse gas, methane, into the atmosphere, amounting to just 2 or 3 kilograms per day per vent. In contrast to controlled methane generate for biofuel ...

Aerospace Manufacturing in Mexico is the Subject of Offshore Group Podcast

Aerospace Manufacturing in Mexico is the Subject of Offshore Group Podcast
2011-07-12
Carlos Bello, executive director of the Mexican Federation of Aerospace Industries, recently sat down with The Offshore Group to discuss the current state of affairs in Mexico's rapidly developing aerospace sector. During the session, Bello informed that Mexico is currently home to 232 aerospace and aerospace industry related companies that employ a combined 29,000 workers. According to Bello, "In recent years, aerospace manufacturing in Mexico has been "experiencing a growth rate of about 20% annually, with the exception of 2009, which was a difficult year ...

EARTH: Is there really a minerals crisis?

2011-07-12
Alexandria, VA – China sent the high-tech industry and markets reeling last fall when it blocked exports of raw rare earth minerals to Japan, Europe and the U.S. The sudden severing of rare earths supply was a frightening prospect as the minerals are key ingredients in a broad range of high-tech products, from smartphones to wind turbines and hybrid cars. Although the bans have since been lifted, governments around the world saw the ban as a kind of wake-up call and started looking at ways to develop their own mineral resources — for rare earths as well as basic industry ...

Is a little negativity the best marketing policy?

Is a little negativity the best marketing policy?
2011-07-12
Tel Aviv — Most marketing departments work hard to establish a flawless reputation for their product or service. But new research from Tel Aviv University is showing that perfection is not all it's cracked up to be. Dr. Danit Ein-Gar of Tel Aviv University's Faculty of Management at the Leon Recanati Graduate School of Business Administration, working in collaboration with Baba Shiv and Zakary Tormala from Stanford University, has uncovered the "blemishing effect," a counterintuitive benefit of negative information. When utilized in the right way, she says, a small flaw ...

New study highlights what works in osteoporosis treatment

2011-07-12
TORONTO, Ont., July 11, 2011—More patients are tested and treated for osteoporosis when fracture clinics have someone dedicated to screening for the bone disease, a new study has found. Those patients also do better when the clinic actually provides bone mineral density (BMD) testing or prescription drug treatment as part of its program rather than just referring fracture patients elsewhere. Researchers at St. Michael's Hospital led by Joanna Sale, a clinical epidemiologist, reviewed osteoporosis screening and management programs involving patients treated for fragility ...

LAST 30 PRESS RELEASES:

Sensing sickness

Cost to build multifamily housing in California more than twice as high as in Texas

Program takes aim at drinking, unsafe sex, and sexual assault on college campuses

Inability to pay for healthcare reaches record high in U.S.

Science ‘storytelling’ urgently needed amid climate and biodiversity crisis

KAIST Develops Retinal Therapy to Restore Lost Vision​

Adipocyte-hepatocyte signaling mechanism uncovered in endoplasmic reticulum stress response

Mammals were adapting from life in the trees to living on the ground before dinosaur-killing asteroid

Low LDL cholesterol levels linked to reduced risk of dementia

Thickening of the eye’s retina associated with greater risk and severity of postoperative delirium in older patients

Almost one in ten people surveyed report having been harmed by the NHS in the last three years

Enhancing light control with complex frequency excitations

New research finds novel drug target for acute myeloid leukemia, bringing hope for cancer patients

New insight into factors associated with a common disease among dogs and humans

Illuminating single atoms for sustainable propylene production

New study finds Rocky Mountain snow contamination

Study examines lactation in critically ill patients

UVA Engineering Dean Jennifer West earns AIMBE’s 2025 Pierre Galletti Award

Doubling down on metasurfaces

New Cedars-Sinai study shows how specialized diet can improve gut disorders

Making moves and hitting the breaks: Owl journeys surprise researchers in western Montana

PKU Scientists simulate the origin and evolution of the North Atlantic Oscillation

ICRAFT breakthrough: Unlocking A20’s dual role in cancer immunotherapy

How VR technology is changing the game for Alzheimer’s disease

A borrowed bacterial gene allowed some marine diatoms to live on a seaweed diet

Balance between two competing nerve proteins deters symptoms of autism in mice

Use of antifungals in agriculture may increase resistance in an infectious yeast

Awareness grows of cancer risk from alcohol consumption, survey finds

The experts that can outsmart optical illusions

Pregnancy may reduce long COVID risk

[Press-News.org] Epigenetic pathway and new drug show promise in reversing a hard-to-treat childhood cancer
Mixed lineage leukemias rely on epigenetic changes to grow and survive; new molecule shows promise for targeting these changes therapeutically